Overall survival by <i>IDH2</i> mutant allele (R140 or R172) in patients with late-stage mutant-<i>IDH2</i> relapsed or refractory acute myeloid leukemia treated with enasidenib or conventional care regimens in the phase 3 IDHENTIFY trial.
Authors: Stéphane De Botton, Alberto Risueño, Andre C. Schuh, Bob Lowenberg, Hee-Je Kim, Paresh Vyas, Andrew H. Wei, Eytan M. Stein, Hartmut Dohner, Amir Tahmasb Fathi, Courtney Denton Dinardo, Patricia Martin Regueira, Lilia Taningco, Iryna Bluemmert, Xin Yu, Wendy L. See, Maroof Hasan
Journal: Journal of Clinical Oncology (2022)

7005 Background: IDH2 gene mutations (m IDH2) occur in up to ̃20% of patients (pts) with acute myeloid leukemia (AML), most commonly as R140Q (in ̃75% of cases) or R172K (̃25%) point mutations. The functional effects and prognostic relevance of m IDH2-R140 and m IDH2-R172 can vary (Papaemmanuil 2016). In the randomized, phase 3 IDHENTIFY trial, enasidenib (ENA), an oral mIDH2 inhibitor, did not significantly improve overall survival (OS) vs conventional care regimens (CCR) as salvage treatment (Tx) for older pts with m IDH2 relapsed/refractory (R/R) AML in ITT analysis, but a trend for improved OS with ENA was detected in pts with IDH2-R172 mutations. We further investigated OS and correlative biomarkers in IDHENTIFY pt subgroups defined by m IDH2 variant (R140/R172). Methods: This open-label trial (NCT02577406) enrolled pts ≥ 60 years of age who had received 2 or 3 prior AML Tx. Pts were preselected to a CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care), and were then randomized 1:1 to ENA 100 mg/d or CCR in 28d cycles. Co-occurring gene mutations were identified by targeted next-generation sequencing (37-gene panel) of bone marrow mononuclear cell (BMMC) DNA. Total 2-HG levels were determined by LC/MS. Results: Of 319 pts enrolled, 88 pts (28%; 43 ENA, 45 CCR) had m IDH2-R172 and 229 (72%; 115 ENA, 114 CCR) had m IDH2-R140. Median baseline (BL) 2-HG levels were similar between Tx arms and m IDH2 variant subgroups, as were IDH2 variant allele frequencies. Pts with m IDH2-R172 had fewer median BL co-mutations (4 [range 2–8]) than did pts with m IDH2-R140 (5 [1–11]) ( P &lt; 0.0001). The most frequently co-occurring mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with the R172 cohort, the R140 group was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2 mutations, whereas DNMT3A and TP53 mutations were more common in the R172 group. In Cox multivariate analysis including m IDH2 variant (R140/R172), DNMT3A mutation status, and number of gene mutations at BL, m IDH2-R172 was significantly ( P = 0.04) correlated with improved OS (vs. R140) in the ENA arm, whereas the number of BL gene mutations was significantly ( P &lt; 0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 mo with ENA vs 7.8 mo with CCR (HR, 0.59 [95%CI 0.35-0.98]; P = 0.039) and 1-yr survival rates were 62% and 30%, respectively. In m IDH2-R140 pts, median OS was 5.7 mo in both Tx arms (0.93 [0.70-1.24]; P = 0.61), and 1-year survival rates were 29% and 25% with ENA and CCR, respectively. Conclusions: Mutational burden and co-mutational profiles differed between pts with m IDH2-R140 and m IDH2-R172 R/R AML. ENA improved survival outcomes for pts with IDH2-R172 mutations, with median OS and 1-year survival rate approximately double those in the CCR arm. Clinical trial information: NCT02577406.